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µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.
Learn More >The wide heterogeneity of available cannabis products makes it difficult for physicians to appropriately guide patients. In the current study, our objective was to characterize naturalistic cannabis use routines and explore associations between routines and reported benefits from consuming cannabis.
Learn More >The experimental investigations on the pathogenesis of remifentanil-induced hyperalgesia (RIH) have been primarily conducted, but the effective treatment of RIH remains unclear. Recent reports highlight the necessity of ionotropic glutamate receptors in oxidative damage in spinal nociceptive transduction. Artesunate, the 1-line anti-malaria drug, has been identified to be valid in removing superoxide in several pathological conditions. This study evaluated whether artesunate inhibits RIH via regulating metabotropic glutamate receptor 5 (mGluR5) and mitochondrial antioxidant enzyme peroxiredoxin-3 in rats. Artesunate was injected intrathecally 10 minutes before intravenous infusion of remifentanil (1μg·kg·minfor 60 minutes) in rats. The antinociception of artesunate was verified by assessment of paw withdrawal mechanical threshold and paw withdrawal thermal latency. Spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation were examined. Also, both the mGluR5 agonist DHPG and antagonist MPEP were utilized to explore the involvement of mGluR5 in the anti-hyperalgesic property of artesunate. Here, we found that artesunate (10μg and 100μg but not 1μg) prevented RIH in a dose-dependent manner. Artesunate reduced remifentanil-related spinal over-expression of mGluR5 gene and protein, and hyperacetylation of peroxiredoxin-3. Intrathecal application of MPEP (10nmol and 100nmol but not 1nmol) inhibited behavioral RIH and peroxiredoxin-3 acetylation. Moreover, hyperalgesia and peroxiredoxin-3 hyperacetylation were attenuated after the combination of artesunate (1μg) and MPEP (1nmol). Additionally, artesunate treatment reversed acute pain and peroxiredoxin-3 hyperacetylation following spinal exposure to DHPG. In conclusion, intrathecal injection of artesunate impairs RIH by down-regulating spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation-mediated oxidative stress in rats.
Learn More >Irritable bowel syndrome (IBS) is a functional gut disorder with multi-factorial pathophysiology that causes recurring pain or discomfort in the abdomen, as well as altered bowel habits. Montelukast, a well-known cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is widely used for the anti-inflammatory management of asthma. The present study aimed to evaluate the effects of pharmacological inhibition of CysLT1R on acetic acid-induced diarrhea-predominant IBS (D-IBS) in rats. Behavioral pain responses to noxious mechanical stimulation were decreased in the montelukast-treated rats as compared to the model animals following colorectal distension (CRD)-induced visceral hypersensitivity. Stool frequency decreased dose-dependently by montelukast in IBS rats exposed to restraint stress. A significantly shorter immobility time was also observed in IBS rats who received montelukast vs IBS group in the forced swimming test (depression-like behavior). Furthermore, there were significant decreases in the NF-κB protein expression, inflammatory cytokine (TNF-α, and IL-1ß) levels, and histopathological inflammatory injuries concomitant with increased anti-inflammatory cytokine, IL-10, in montelukast-treated rats compared with the IBS group. Cysteinyl leukotriene production and CysLT1R mRNA expression showed no remarkable differences among the experimental groups. The present results suggest the possible beneficial effects of montelukast in the management of D-IBS symptoms. The molecular mechanism underlying such effects, at least to some extent, might be through modulating CysLT1R-mediated NF-κB signaling. Yet, more studies are required to demonstrate the clinical potential of this drug for IBS therapy.
Learn More >Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes.
Learn More >The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra™), a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behaviour and pronociceptive signalling in dorsal root ganglia (DRG) and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, increased PI3K/Akt-signalling in small-diameter DRG neurons and an increase of CD68 cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA approved drug with known side effects.We show that duvelisib, a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behaviour in males and females and prevents pronociceptive signalling in dorsal root ganglia and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.
Learn More >Neuropathic pain is the most prevalent form of chronic pain caused by a disease of the nervous system, such as diabetic polyneuropathy. ɑ-Lipoic acid (ALA) is an antioxidant that has been widely studied for the treatment of pain symptoms in diverse conditions. Therefore, this study aimed to investigate the efficacy of ALA in the treatment of different types of pain through a systematic review and meta-analysis of randomized clinical trials. The study protocol was registered in the International Prospective Registry of Systematic Reviews (CRD42021261971). A search of the databases resulted in 1154 articles, 16 of which were included in the review (9 studies with diabetic polyneuropathy and 7 studies with other painful conditions). Most of the included studies had a low risk of bias. ALA showed efficacy for the treatment of headache, carpal tunnel syndrome and burning mouth syndrome. Meta-analysis was conducted only with the studies using diabetic polyneuropathy. Compared to placebo, ALA treatment decreased the total symptom score (TSS). The subgroup meta-analysis indicated a decrease of stabbing pain, burning, paraesthesia, and numbness in ALA-treated patients compared to placebo. In addition, both routes of administration, intravenous and oral, demonstrated the efficacy to reduce TSS. Therefore, ALA should be used to treat diabetic polyneuropathy pain symptoms. However, the standardization of treatment time and the dose may advance for the approval of ALA for clinical use in diabetic polyneuroneuropathy.
Learn More >Opioid-induced hyperalgesia (OIH) is a problem associated with prolonged use of opioids in chronic pain management, and its effective treatment has been hampered by lack of mechanistic evidence. Oligodendrocytes have recently been linked with several pain-related diseases; however, little is known its role in OIH. The prelimbic medial prefrontal cortex (PL-mPFC) has emerged as a significant center of pain regulation, and is rich in oligodendrocytes. Herein we explored the effect of oligodendrocyte apoptosis of PL-mPFC on OIH. Using a fentanyl-induced rat model of OIH and proteomics analysis of the PL-mPFC, we observed a downregulation in five types of myelin-related proteins originating from oligodendrocytes; this was further verified by western blotting. Meanwhile, cleaved-caspase 3 (an apoptosis marker) was increased, whereas the oligodendrocyte precursor cell (OPC) marker NG2 remained unchanged. These results suggest that downregulated myelin-related proteins may be associated with oligodendrocyte apoptosis rather than a reduction in their generating source, and immunohistochemistry confirmed this hypothesis. Behaviorally, prophylactic blockade of oligodendrocyte apoptosis by microinjection of z-DEVD-fmk into the PL-mPFC prevented fentanyl-induced mechanical and thermal hyperalgesia, but downregulated myelin basic protein (mbp) gradually recovered in 12 h. We suggest that OIH may be primed in part via oligodendrocyte apoptosis in the PL-mPFC. PERSPECTIVE: : In this study we showed that oligodendrocyte apoptosis in the PL-mPFC is a key trigger for fentanyl-induced hyperalgesia. Targeting oligodendrocyte apoptosis in the PL-mPFC may prevented hyperalgesia priming induced by fentanyl.
Learn More >Inactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases.
Learn More >Ultrasound-guided hydrodissection with 5% dextrose in water (DW5) creates a peri-nervous compartment, separating the nerve from the neighboring anatomical structures. The aim of this randomized study was to determine the minimum volume of lidocaine 2% with epinephrine 1:200,000 required when using this technique to achieve an effective median nerve block at the elbow in 95% of patients (MEAV95). Fifty-two patients scheduled for elective hand surgery received an ultrasound-guided circumferential perineural injection of 4 ml DW5 and an injection of local anesthetic (LA) following a biased coin up-and-down sequential allocation method. A successful block was defined as a light touch completely suppressed on the two distal phalanges of the index finger within a 30-min evaluation period. The MEAV95 of lidocaine 2% with epinephrine was 4 ml [IQR 3.5-4.0]. Successful median nerve block was obtained in 38 cases (82.6%) with median onset time of 20.0 [10.0-21.2] minutes (95% CI 15-20). The analgesia duration was 248 [208-286] minutes (95% CI 222-276). Using an ultrasound-guided hydrodissection technique with DW5, the MEAV95 to block the median nerve at the elbow with 2% lidocaine with epinephrine was 4 ml [IQR 3.5-4.0]. This volume is close to that usually recommended in clinical practice.Trial registration clinicaltrials.gov. NCT02438657, Date of registration: May 8, 2015.
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